Base-mediated cascade amidination/: N -alkylation of amines by alcohols

Article abstract of DOI:10.1039/d0cc04831c

A base-mediated cascade amidination/N-alkylation reaction of amines by alcohols has been developed. For the first time, nitriles have been identified as an efficient and benign water acceptor reagent in N-alkylation. Notably, the procedure tolerates a series of functional groups, such as methoxyl, halo, vinyl and hetero groups, providing a convenient method to construct different substituted diamino compounds, 15N labeled amine and could be scaled up to 1 mol scale offering 138.7 g of the desired product in good yield in one-pot. Mechanistic studies provided strong evidence for the amidination of amines with nitriles facilitated by t-BuOK.

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Base mediated cascade amidination/N-alkylation of amines by alcohols
Chunyan Zhang,*,a Zuyu Liang,a Fenghong Lu,a Xiaofei Jia,a Guoying Zhang*,a and Mao-Lin Hu*,b
Received (in XXX, XXX) Xth XXXXXXXXX 202X, Accepted Xth XXXXXXXXX 202X
First published on the web Xth XXXXXXXXX 202X
DOI: 10.1039/b000000x
5
A base-mediated cascade amidination/N-alkylation reaction of
or capricious ligands are in most cases required to sustain the
amines by alcohols has been developed. Nitriles has been 45 catalytic cycle, which generally are not readily accessible,
identified as an efficient and benign water acceptor reagent for
the first time in the N-alkylation. Notably, the procedure
10 tolerates a series of functional groups, such as methoxyl, halo,
vinyl and hetero groups, providing a convenient method to
manipulations and toxic (Scheme 1, top).5 Thus, the development
of efficient, economic, even metal catalyst or ligand free
processes is still a challenging task in this field. One attractive
approach to circumvent this problem is to employ the sole base or
construct the different substituted diamino compounds, 15N 50 organic additive for realizing N-alkylation transformation.
labeled amine and could scaled up to 1 mol scale offered 138.7 g
desired product in good yield in one-pot. Mechanistic studies
15 provided strong evidence of amidination of amines with nitriles
facilitated by t-BuOK.
Recently, we have identified that t-BuOK can deal with
alcohols to generate alkoxide species and manganese-catalyzed
olefination of alkyl-substituted N-heteroarenes with alcohols.6
These results together with our progress on the use of alcohols as
55 the replacement of sustainable green substrates for N-alkylation,7
prompted us to envision that amines might be transformed to
amidines for circumvent the inherent necessary in the metal
catalyzed alkylation with catalyst stabilized by ligand for
activated alcohols to maintain catalytic cycle.8 Specifically, we
60 postulated that the metathesis process of the intermediate amidine
generated in situ from the amine with nitrile under the base
promoted to alcohol gave the desired product, realizing nitriles as
a water acceptor for sustain the transformation (Scheme 1,
bottom). Moreover, to the best of our knowledge, there is no
65 reaction system dealing with nitriles as water acceptor for the N-
alkylation has been disclosed. Herein, we describe the first base
mediated amidination/N-alkylation of amines by alcohols that
employs nitriles as an efficient benign water acceptor.
As one of the most important fundamental structural motifs,
amines has been considered as a privileged structure in natural
products, bioactive molecules and functional materials.1 As such,
30 the development of efficient procedures toward these molecules
is of great significance to chemical and material science and has
attracted plenty of attention over the past decades.2
Previous work:
[M]
R'
N
R
O
H
R
H
[M]
activation
of alcohol
metal catalyzed
N-alkylation
[MH2]
NH2
R'
R
O
N
R
R
R'
This work:
R'
R1-CN
R'
Table 1 Screening the best nitriles receptor a
NH2
N
H
t-BuOK
Ph
R1-CN
R1C(O)NH2
activation
of amine
cascade
amidination-
N
H2
Ph
N
H
C1
+
Ph
Ph
OH
A1
1,4-dioxane
B1
N-alkylation
H
O
H
NH
N
R
HO CN
R'
CH3CN
CN
D2
Ph NCS Ph NCO
D5 D6
C1 C1
R1
N
R1
NM
R'
CN
O
H
R
H
D1
D3
D4
C1
C1
C1
C1
, <5%
, <5%
, <5%
, <5%
, 0
, 0
Scheme 1 State of the art and the reaction described here.
NC
CN
CN
CN
CN
CN
35
Metal catalyzed borrowing of hydrogen methodology (BH/HA)
has become appealing way to offered versatile amines, which on
account of the sustainable green features of the readily available
alcohol substrates (its could abundant supply from indigestible
lignocellulose biomass degradation) and advantages over the
OCH3
D8
CH3
D9
, 94%
D7
D10
D11
D12
, 14%
C1
C1
C1
C1
C1
C1
, 0
, 95%
, 81%
, 45%
40 halide substrates.3 Mechanistically, metal catalyzed N-alkylation
functionalization is a thermodynamically unfavorable procedure,
because of initial dehydrogenative alcohol converted to active
hydridometal species and aldehyde.4 Therefore, complex catalysts
CN
CN
CN
CN
CN
CN
Cl Cl
Cl
Cl
Cl
D14
NO2
D18
a
Key Laboratory of Sensor Analysis of Tumor Marker, Ministry of Education;
D13
C1
D15
C1
D16
C1
D17
Shandong Key Laboratory of Biochemical Analysis; Key Laboratory of Analytical
Chemistry for Life Science in Universities of Shandong; College of Chemistry and
Molecular Engineering. Qingdao University of Science and Technology, Qingdao
266042, P.R. China. E-mail: zhanggy@qust.edu.cn
C1
C1
C1
, 62%
, 96%
, 81%
, 70%
, 31%
, 12%
70
a Reaction conditions: A1 (1.0 mmol), B1 (0.5 mmol), D (0.8 mmol), t-
BuOK (0.8 mmol), 1,4-dioxane (2.0 mL), 120 C, N2, 15 h. Yield of C1
determined by GC-analysis.
o
b College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou
325035, P.R. China. E-mail: maolin_hu@yahoo.com
†
Electronic supplementary information (ESI) available. See DOI:
10.1039/0000000x/
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To probe the validity of our hypothesis, we examined the
obvious impact on the efficacy of the transformation, affording
possibility of the N-alkylation of aniline by phenyl methanol 35 C5 and C8 in decrease yields. Naphthalen-1-amine was surveyed
with various nitriles as water acceptor (Table 1). After finding
initial reaction conditions, different organic compounds with
the groups contain of ‘CN’ were tested to find the most active
nitriles. Only a trace amount of the desired C1 was detected
and the reaction proceeded to give C9 in 70% yield. Heterocyclic
C10 could be obtained in good yield under standard conditions.
C11 was isolated in reasonable yield with biphenyl methanol
substrate. Furthermore, aliphatic alcohols were less reactive and
5
with
alkyl
substituted
nitriles
(D1-D4). 40 acceptable amount products C12-C14 were formed when the
Isothiocyanatobenzene,
isocyanobenzene as the acceptor, the alkylation product was
isocyanatobenzene
or
reaction was conducted at high temperature for extension of
reaction time.
10 unfounded. Nitriles functionalized with the aromatic groups
(D8-D18) gave the better yields of C1. Further investigation
revealed that the reactivity was affected by the electronic and
steric nature of the substituted groups of aromatic nitriles, and
the sequence activity was electron-donating > withdrawing
15 groups; para > meta > ortho. Thus benzonitrile was chosen as
the relatively cheap acceptor. In addition, the best yield of C1
was obtained after thoroughly optimization of the reaction
parameters (type of base, amount of base, type of solvent,
substrate ratio, reaction temperature and time) with D13.9
Table 3 N-alkylation of phenyl methanol with various amines a
t-BuOK
R
N
H2
R
N
+
Ph
Ph
OH
H
D13
A1
B15-32
C15-32
H
H
H
N
N
Ph
Ph
Ph
Ph
N
Ph
Br
I
Cl
C15
C18
C16
C19
C17
, 84%
, 68%
, 43%
H
H
H
N
N
N
Ph
20 Table 2 N-alkylation of aniline with various alcohols a
Et
NC
C20
C23
, 26%
, 90%
, 71%
H
t-BuOK
Ph
H
N
H2
Ph
N
H
C1-14
+
R
R
OH
H
N
Ph
N
Ph
N
Ph
D13
A1-14
B1
Ph
Ph
N
Ph
Ph
Ph
N
N
C21
C22
C25
, 83%
, 58%
, 70%
H
H
H
H
H
Cl
Br
N
Ph
H
N
MeO
Ph
S
N
Ph
C1
C4
C2
C5
C3
, 91%
, 82%
, 70%
, 90%
Ph
N
Ph
Ph
Ph
N
H
MeO
N
H
C24
C27
C26
C29
, 90%
, 76%
, 83%
H
H
H
H
N
Ph
N
N
Ph
Ph
Br
Ph
C6
C9
, 84%
, 68%
O
Ph
N
N
N
Ph
Ph
H
N
N
C28
, 66%
, 75%
, 60%
H
H
O
H
H
H
N
N
N
Ph
Ph
C7
C8
, 92%
, 69%
Ph
, 70%
N
N
Ph
Ph
S
N
C30, 73%
C31, 81%
C32, <5%b
N
N
H
H
H
a
45 Reaction conditions: A1 (1.0 mmol), B15-32 (0.5 mmol), D13 (0.8
mmol), t-BuOK (0.8 mmol), 1,4-dioxane (2.0 mL), 120 oC, N2, 15 h.
b
b
C10
C11
C12
, 80%
, 36%
, 41%
b
Isolated yield. A1 (3.0 mmol), D13 (2.0 mmol), t-BuOK (2.0 mmol),
150 oC (carried out in the autoclave), 48 h.
Ph
N
Ph
H
N
Subsequent, investigation of the scope regarding the amines
50 was undertaken in Table 3. For most of the substituted anilines,
the transformation proceeded smoothly to offer the corresponding
products in moderate to excellent yields. The conversion could be
compatible with a wide range of functional groups such as halo,
cyano, alkyl, alkyloxy and thienyl groups, showing that the
55 present reaction had a good functional groups tolerance. Lower
yields were obtained substituted with electron-withdrawing
groups than electron-donating ones on aromatic ring. Halide
groups particularly, even iodo, survived well in the standard
procedure, leading to corresponding adducts C15-C17 in
60 acceptable to good yields. The orientation of substituents of
amines had slight impact on the efficacy of the conversion,
affording the C20, C22 and C23 in decrease yields. Interestingly,
the (E)-4-styrylaniline reacted rendering the target amine C27 in
H
b
b
C13
, 53%
C14
, 40%
a Reaction conditions: A1-14 (1.0 mmol), B1 (0.5 mmol), D13 (0.8 mmol),
t-BuOK (0.8 mmol), 1,4-dioxane (2.0 mL), 120 oC, N2, 15 h. Isolated
yield. b A (2.0 mmol), D13 (1.0 mmol), 130 oC, 48 h.
25
With the optimized N-alkylation conditions in hand, initially,
we examined the substrate scope of alcohols for the synthesis of
N-substituted anilines (Table 2). Alcohols containing various
electron rich and inefficient aromatic functional groups reacted
smoothly to produce the corresponding products in good to high
30 yields. The aryl halide substituent remained intact during this
reaction (C2, C3), providing the N-alkylation adducts in high
yields and a useful handle for further elaboration. The orientation
of substituents on the aromatic ring system of alcohols had an
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acceptable yield. Some heterocyclic moieties, including 2-
pyridine, functionalization 2-pyridines and 3-pyridine, could be
smoothly incorporated in the corresponding products C28-C31.
to incorporate 15N into amine molecules (eq 3).
More experiments were carried out for better understanding of
the mechanism (Scheme 3). Initially, we examined a series of
Unfortunately, only trace amount of desired product was founded 40 reaction conditions (ultra-pure substrates) using the new reaction
5
with aliphatic amine as partner even the reaction was even
conducted under high temperature.
tube, there was no impact on yield of C1, indicating this
transformation should not involve a transition metal catalyzed
process (eq 1). Furthermore, only trace amounts or low yield of
the C1 was obtained in the presence of 18-crown-6 (eq 2),
45 attributing to the strong complexation ability of 18-crown-6 with
the potassium cation.10 In addition, C1 was obtained in good
yield when tetramethylpiperidin-1-oxyl or ethene-1,1-
diyldibenzene were added into the standard reaction as radical
scavenger, showing that this reaction should not be a free radical
50 process (eq 3). These results demonstrated that the significant
role of the base and nitrile in promoting this transformation the
N-alkylation rather than metal catalysts or its impurities.
Table 4 N-alkylation of various alcohols with different amines a
R2
t-BuOK
R1
R2
N
R1 OH
N
+
H2
H
D13
A
B
C33-39
OMe
SMe
Cl
H
H
H
N
N
N
C33
, 81%
C34
N
, 82%
C35
, 79%
N
N
Cl
H
N
H
N
standard conditions
Ph
N
H2
Ph
N
+
Ph
C1
Ph
OH
(1)
new tube
pure substrates
H
C36
, 40%
C37
, 71%
I
A1
A1
B1
, 93%
standard conditions
Ph
(2)
N
H2
Ph
N
+
Ph
Ph
OH
N
N
H
b
N
N
H
H
H
H
B1
C1
, 28%
C1
, <5%
with 18-crown-6 (0.5 equiv);
with 18-crown-6 (2 equiv);
C38
C39
, 66%
, 73%
OMe
a Reaction conditions: A (1.0 mmol), B (0.5 mmol), D13 (0.8 mmol), t-
Ph
standard conditions
N
H2
Ph
N
+
Ph
Ph
OH
10 BuOK (0.8 mmol), 1,4-dioxane (2.0 mL), 120 oC, N2, 15 h. Isolated yield.
(3)
, 78%
, 81%
H
b A1 (3.0 mmol), B1 (1.0 mmol), D13 (2.0 mmol), 120 oC, 36 h.
A1
B1
C1
C1
TEMPO (2 equiv);
Ph2C=CH2 (2 equiv);
Furthermore, the N-alkylation of different substituent amines
with various alcohols were also studied (Table 4). Alcohols
bearing alkyl, alkyloxy and methylthio substituents derived from
15 aromatic alcohols were effective substrates to react with pyridin-
3-amine to provide the corresponding products C33-C35 in good
to high yields. Iodo and alkenyl substituted amines with (4-
chlorophenyl)methanol underwent the N-alkylation process to
give the desired products C36-C37 in acceptable to good yields.
NH
t-BuOK
(4)
N
PhCN
+
H2
Ph
Ph
Ph
N
1,4-dioxane
D13
B1
H
E1
E1
without t-BuOK;
, <5%
, 41%
t-BuOK (0.8 mmol);
t-BuOK
1,4-dioxane
t-BuOK (0.8 mmol);
NH
Ph
+
(5)
N
Ph
Ph
OH
Ph
H
Ph
N
H
A1
E1
C1
, 82%
20 Furthermore,
the
N1-hexylbenzene-1,3-diamine
reacted
C1
E1
without t-BuOK;
, 0%,
recovered 91%
successfully rendering the target amine C38 in good yield.
Interestingly, double alkylation occurs when benzene-1,3-
diamine was subjected to the present reaction, providing C39
with double amino groups in 66% yield.
1. t-BuOK
2. t-BuOK
Ph
(6)
PhCN
D13
+
N
H2 Ph
B1
N
Ph
H
1,4-dioxane
A1
C1
, 84%
t-BuOK
t-BuOK
E1
M
O-
NK
N
A1
Ph
(7)
A1, D13
A7, D13
2.
1.
C1
Ph
N
H
TS-E1
(1)
OMe
N
Ph
H
Ph
N
Ph
N
t-BuOK
NH2
t-BuOK
B1 D13
+
H2N
H
H
Ph
TS-E2
C40
, 51%
O
Scheme 3 Mechanistic investigations.
t-BuOK
Ph
N
H2
Ph
+
Ph
N
+
Ph
OH
(2)
55
In addition, N-phenylbenzimidamide E1 could be isolated 41%
yield under the standard conditions, only trace amount of E1 was
detected in absence of base (eq 4). Further E1 with A1 could be
transformed into C1 in good yield at the same reaction conditions,
but no reaction in absence of t-BuOK and E1 could be recovered
H
D13
Ph
NH2
A1
2000 mmol
B1
C1
72% (137.8 g)
1000 mmol
90% (108.9 g)
H
15N
Standard conditions
15N
15N-B1
Ph
15N-C1
+
OH
Ph
H2
Ph
(3)
Ph
, 88%
A1
25
60 in high yield (eq 5). Meanwhile, C1 was obtained in 84% yield
by step by step reaction (eq 6). Furthermore, E1 and byproduct
benzamide were detected during the reaction, and the yield of E1
and benzamide at different reaction times are outlined in Figure
1.9 These results showed that N-phenylbenzimidamide E1 (in situ
65 form is TS-E1) may be the intermediate since the transformation
of E1 to C1 via TS-E2 was observed in Figure 1 and further
confirmed our previous work.7b
Scheme 2 Application of N-alkylation.
The cascade N-alkylation of benzene-1,3-diamine with A1
and A7 in the presence of appropriate amount of nitrile to
form the C40 in moderate yield, which can be used for to
30 construct the different substituted diamino compounds and
further transformations to complex amines molecules.
Hereafter, we scaled up the transformation to 1 mol scale and
product C1 was recrystallized in 72% (137.8 g) with 90%
(108.9 g) yield of byproduct benzamide. Subsequently, the
35 15N-labeled N-benzyl aniline (15N-C1) was formed when 15N-
labeled aniline was utilized, providing a convenient stratagy
Conclusions
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Zhao, J.-L. Hou and Z.-T. Li, Chem. Rev., 2012, 112, 5271; (f) E. B.
Divito and M. Cascio, Chem. Rev., 2013, 113, 7343; (g) X.-F. Wu, H.
Neumann and M. Beller, Chem. Rev., 2013, 113, 1; (h) X.- F. Wu, X.
Fang, L. Wu, R. Jackstell, H. Neumann and M. Beller, Acc. Chem.
Res., 2014, 47, 1041; (i) X. Guo, A. Facchetti and T. J. Marks, Chem.
Rev., 2014, 114, 8943; (j) D.-W. Zhang, X. Zhao and Z.-T. Li, Acc.
Chem. Res., 2014, 47, 1961.
(a) E. D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797; (b) I.
Sorribes, K. Junge and M. Beller, J. Am. Chem. Soc., 2014, 136, 14314; (c)
I. Sorribes, J. R. Cabrero-Antonino, C. Vicent, K, Junge and M. Beller, J.
Am. Chem. Soc., 2015, 137, 13580; (d) M.-C. Fu, R. Shang, W.-M. Cheng
and Y. Fu, Angew. Chem. Int. Ed., 2015, 54, 9042; (e) M. Mastalir, M.
Glatz, E. Pittenauer, G. Allmaier and K. Kirchner, J. Am. Chem. Soc.,
2016, 138, 15543; (f) N. Deibl and R. Kempe, Angew. Chem. Int. Ed.,
2017, 56, 1663; (g) S. Fu, Z. Shao, Y. Wang and Q. Liu, J. Am.
Chem. Soc., 2017, 139, 11941; (h) A. Kumar, N. A. Espinosa-Jalapa,
G. Leitus, Y. Diskin-Posner, L. Avram and D. Milstein, Angew.
Chem. Int. Ed., 2017, 56, 14992; (i) J. Sebastian, M. Zheng, Y. Jiang, Y.
Zhao, H. Wang, Z. Song, X. Li, J. Pang and T. Zhang, Green Chem., 2019,
21, 2462; (j) M. Huang, Y. Li, Y. Li, J. Liu, S. Shu, Y. Liu and Z. Ke.
Chem. Commun., 2019, 55, 6213; (k) P. Yang, C.Zhang, W.-C. Gao,
Y. Ma, X. Wang, L. Zhang, J. Yue and B. Tang, Chem. Commun.,
2019, 55, 7844.
In summary, we have demonstrated an efficient protocol for
the t-BuOK mediated cascade amidiation/N-alkylation of
amines by alcohols. Importantly, the reaction employs nitriles
as an inexpensive and benign water acceptor. Furthermore,
this transformation is very practical, and a series of functional
groups could be tolerated. As such, it represents a novel and
simple method to access the different substituted monoamino,
diamino compounds, 15N labeled amine molecule and could
scaled up to 1 mol scale. Further studies aimed at gaining a
50
55
5
3
10 detailed mechanistic understanding of this N-alkylation and
the application of base as the efficiently mediator in other
transformations are currently in progress in our laboratory.
60
65
4
(a) J. M. Humphrey and A. R. Chamberlin, Chem. Rev., 1997, 97,
2243; (b) S. Eichner, T. Eichner, H. G. Floss, J. Fohrer, E. Hofer, F.
Sasse, C. Zeilinger and A. Kirschning, J. Am. Chem. Soc., 2012, 134,
1673; (c) N. A. Espinosa-Jalapa, A. Kumar, G. Leitus, Y. Diskin-
Posner and D. Milstein, J. Am. Chem. Soc., 2017, 139, 11722; (d) F.
Kallmeier, B. Dudziec, T. Irrgang and R. Kempe, Angew. Chem. Int.
Ed., 2017, 56, 7261; (e) M. Mastalir, E. Pittenauer, G. Allmaier and
K. Kirchner, J. Am. Chem. Soc., 2017, 139, 8812; (f) S. Chakraborty,
U. Gellrich, Y. Diskin-Posner, G. Leitus, L. Avram and D. Milstein,
Angew. Chem. Int. Ed., 2017, 56, 4229; (g) N. V. Kulkarni and W. W.
Brennessel, W. D. Jones, ACS Catal., 2018, 8, 997; (h) B. Wang, S.
Ma, S. Yan and J. Zhu, Green Chem., 2019, 21, 5781; (i) V. Botla, N.
Pilliab and C. Malapaka, Green Chem., 2019, 21, 1735.
70
75
Figure 1 Distribution along with the reaction time.
15 Conflicts of interest
80
There are no conflicts of interest to declare.
5
(a) R. Grigg, T. R. B Mitchell, S. Sutthivaiyakit, N. Tongpenyai, J.
Chem. Soc. Chem. Commun., 1981, 611; (b) R. R. Donthiri, R. D.
Patil and S. Adimurthy, Eur. J. Org. Chem., 2012, 24, 4457; (c) X.
Han and J. Wu, Angew. Chem. Int. Ed., 2013, 52, 4637; (d) R. R.
Donthiri, V. Pappula and S. Adimurthy, J. Org. Chem., 2013, 78,
6775; (e) Q. Xu, J. Chen and H. Tian, Angew. Chem. Int. Ed., 2014,
53, 225; (f) X. Lu, Y. Sun and Q. Xia, Catal. Commun., 2014, 55, 78;
(g) S. Li, X. Li, Q. Xu, Green. Chem., 2015, 17, 3260; (h) Q. Li, Z.
Xiao and Y. Kang, Org. Lett., 2015, 17, 5328; (i) Z.-Y. Tian and C.-P.
Zhang, Chem. Commun., 2019, 55, 11936; (j) H. Zeng, J. Yu and C.-J.
Li, Chem. Commun., 2020, 56, 1239.
Acknowledgements
85
This research was supported by the National Natural
Science Foundation of China (No. 21571143), the Shandong
20 Provincial Natural Science Foundation of China (Nos.
ZR2017MB029, ZR2017BB060), the Qingdao Science
and Technology Foundation (18-2-2-49-jch) for financial
support.
90
6
7
(a) G. Zhang, T. Irrgang, T. Dietel, F. Kallmeier and R. Kempe,
Angew. Chem. Int. Ed., 2018, 57, 9131. (b) C. Zhang, G. Zhang, S.
Luo, C. Wang and H. Li, Org. Biomol. Chem., 2018, 16, 8467.
(a) Z. Liang, J. Chen, X. Chen, K. Zhang, J. Lv, H. Zhao, G. Zhang,
C. Xie, L. Zong and X. Jia, Chem. Commun., 2019, 55, 13721; (b) C.
Zhang, Z. Li, J. Chen, S. Qi, Y. Fang, S. Zhang, C. Ren, F. Lu, Z.
Liang, S. Jiang, X. Jia, S. Yu and G. Zhang, J. Org. Chem., 2020, 85,
7728.
(a) K. Maruoka and H. Yamamoto, Angew. Chem. Int. Ed., 1985, 24,
668; (b) C. Feuvrie, J. Blanchet, M. Bonin and L. Micouin, Org.
Lett., 2004, 6, 2333; (c) J. U. Jeong, X. Chen, A. Rahman, D. S.
Yamashita and J. I. Luengo, Org. Lett., 2004, 6, 1013; (d) L. E. Kaim,
L. Grimaud, A. Lee, Y. Perroux and Tirla, C. Org. Lett., 2004, 6, 381;
(e) O. Jackowski, T. Lecourt and L. Micouin, Org. Lett., 2011, 13,
5664.
Notes and references
95
25 1 (a) C. Hansch, P. G. Sammes and J. B. Taylor, Comprehensive
Medicinal Chemistry; Pergamon Press: Oxford, UK, 1990, 2, Chapter
7.1; (b) Y. Kaku, A. Tsuruoka, H. Kakinuma, I. Tsukada, M.
Yanagisawa and T. Naito, Chem. Pharm. Bull., 1998, 46, 1125; (c) G.
T. Brooks and T. R. Roberts, Pesticide Chemistry and Bioscience;
100
105
110
30
35
40
45
Royal Society of Chemistry: Cambridge, UK, 1999; (d) J. W. Clader,
J. Med. Chem., 2004, 47, 1; (e) J. W. Bode, Curr. Opin. Drug.
Discovery. Dev., 2006, 9, 765; (f) Q. Zhang, S. M. Keenan, Y. Peng,
A. C. Nair, S. J. Yu, R. D. Howells and W. J. Welsh, J. Med. Chem.,
2006, 49, 4044; (g) R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006,
2, 284; (h) W. Wu, Z. Zhang and L. S. Liebeskind, J. Am. Chem. Soc.,
2011, 133, 14256; (i) X. Wang, F. Meng, Y. Wang, Z. Han, Y.-J.
Chen, L. Liu, Z. Wang and K. Ding, Angew. Chem., Int. Ed., 2012,
51, 9276; (j) H. Noda, G. Erős and J. W. Bode, J. Am. Chem. Soc.,
2014, 136, 5611; (k) A. Bera, M. Sk, K. Singh and D. Banerjee,
Chem. Commun., 2019, 55, 5958.
8
9
See the Supporting Information for details.
10 (a) H. An, J. S. Bradshaw and R. M. Izatt, Chem. Rev., 1992, 92, 543;
(b) J. S. Bradshaw and R. M. Izatt, Acc. Chem. Res., 1997, 30, 338;
(c) G. W. Gokel, W. M. Leevy and M. E. Weber, Chem. Rev., 2004,
104, 2723.
2
(a) L. Crespo, G. Sanclimens, M. Pons, E. Giralt, M. Royo and F.
Albericio, Chem. Rev., 2005, 105, 1663; (b) M. A. L. Mintzer and E.
E. Simanek, Chem. Rev., 2009, 109, 259; (c) U. Boas, J. Brask and K.
J. Jensen, Chem. Rev., 2009, 109, 2092; (d) X.-F. Wu, H. Neumann
and M. Beller, Chem. Soc. Rev., 2011, 40, 4986; (e) D.-W. Zhang, X.
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ChemComm
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DOI: 10.1039/D0CC04831C
Base mediated cascade amidination/alkylation of amines by alcohlos
We have developed an efficient base mediated cascade amidination/N-alkylation of amines by alcohols with
nitriles as a benign water acceptor reagent, providing a convenient method to construct the different substituted
diamino compounds, 15N labeled amine molecules and could scaled up to 1 mol scale.